The assignee hereof has filed a number of applications referring to nordihydroguaiaretic acid (NDGA) and related compounds, and also mixtures of such compounds with metal salts, useful for the treatment of psoriasis, namely U.S. application Ser. No. 578, 501, abandoned, "Pharmacologically Active Mixtures of Organic Compositions and Metal Salts," Jordan, a continuation in part of Ser. No. 465,631, abandoned, being filed in the U.S. Patent Office concurrently herewith; U.S. application Ser. No. 578,549 "Methods of Treating Psoriasis and Inhibiting the Action of Lipoxygenase on Arachidonic Acid," Jordan, also being filed concurrently herewith; and U.S. Ser. No. 365,784, "Modification of Plant Extracts from Zygophyllaceae," Jordan.
The compounds herein are discussed in this assignee's applications filed concurrently herewith entitled "Tumor Reducing Compositions," Allen, and "Antioxidant Compounds and Methods of Synthesis," Allen, et al.
A number of lipoxygenase inhibitors are known. F. Fiebrich, et al., in "Silymarin, an Inhibitor of Lipoxygenase," Experientia 35 (1979) at 1548 report the silymarin marin constituents silybin, silydianin, and silychristin as lipoxygenase inhibitors.
J. Baumanor, et al., "Flavonoids and Related Compounds as Inhibitors of Arachidonic Acid Peroxidation," Prostaglandins, Vol. 20, No. 4, pp. 627-37, October, 1980, list a number of lipoxygenase and cyclo-oxygenase pathway inhibitors and compare their abilities to inhibit each pathway. The most effective lipoxygenase inhibitors listed are 2-aminoethyl-4-t-6-iodophenol (MK447), diphenylthiocarbazone, phenidone, BW 755C, 1,5-dihydroxynaphthalene, 2,3-dihydroxynaphthalene, 1,3-dihydroxynaphthalene, and mefenamic acid, of which the first two appear to have a high degree of specificity for lipoxygenase inhibition. This article also reports that silybin, rutin, tetrahydroxyethlyquercetin, trihydroxyethylquercetin, monohydroxyethylquercetin, and monohydroxyethylrutin predominantly inhibit lipoxygenase, while luteolin, dihydroxyflavone, morin, and galangin inhibit both pathways. K. V. Honn, et al., in "Nafazatrom (Bay g 6575) Inhibition of Tumor Cell Lipoxygenase Activity and Cellular Proliferation," FEBS Letters, Vol. 139, No. 1, pp. 65-68, March, 1982, describe nafazatrom as a selective lipoxygenase inhibitor. R. V. Panganamala, et al, in "Differential Inhibitory Effects of Vitamin E and other Antioxidants in Prostaglandin Synthetase, Platelet Aggregation and Lipoxidase," Prostaglandins, Vol. 14, No. 2, pp. 261-64, August, 1977, describe dl-2-tocopherol, BHT and Trolox C as specific inhibitors of lipoxygenase and describe the following compounds as non-specific inhibitors of lipoxygenase: alpha-naphthol, propyl gallate and NDGA. K. Yasumoto, et al., in "Effect of Phenolic Antioxidants on Lipoxygenase Reaction," Agr. Biol. Chem, Vol. 34, No. 8, pp. 1162-68, 1970, list and rank (in order given) the following compounds as lipoxygenase inhibitors: NDGA, quercetin, propyl gallate, alpha-tocopherol, alpha-naphthol, homocatechol, pyrocatechol, BHA, BHT, hydroquinone, ploroglucinol, pyrogallol, resorcinol. Y. Kosihara, et al., in "Selective Inhibition of 5-Lipoxygenase by Natural Compounds Isolated from Chinese Plants, Artemisia rubripes Nakai," FEBS, Vol. 158, No. 1, p. 41, July, 1983, describe caffeic acid, eupatilin and 4'-demethyleupatilin as selective inhibitors of the 5-lipoxygenase pathway.
A number of compounds structurally similar to arachidonic acid and its derivatives have been disclosed as lipoxygenase inhibitors. M. O. Funk, Jr., et al., in "A New Class of Lipoxygenase Inhibitor. Polyunsaturated Fatty Acids Containing Sulfur," Bioch. and Bioph. Res. Comm., Vol. 114, No. 3, pp. 937-43, 1983, describe 13-thia-9(Z),11(E)-octadecadienoic acid and 13-thia-9(E), 11(E)-octadecadienoic acid as soybean lipoxygenase inhibitors. C. D. Perchonock, et al., in "Dimethyleicosatrienoic Acids: Inhibitors of the 5-lipoxygenase Enzyme," Tetrahedron Letters, Vol. 24, No. 24, pp. 2457-60, 1983, describe 7,7'- and 10,10'-dimethyleicosa-5(Z), 8(Z), 11(Z)-trienoic acids as 5-lipoxygenase inhibitors. J. R. Pfister, et al, in "Synthesis of Three Potential Inhibitors of Leukotriene Biosynthesis," J. Medicinal Chemistry, Vol. 26, No. 8, p. 1100-03, 1983, describe 5,6-benzoarachidonic acid as a 5-lipoxygenase inhibitor. PCT patent application, K. C. Nicolau, "Leukotriene Analogues," filed in the U.S. Nov. 27, 1981, published in the PCT Gazette as No. WO 83/01897 on June 9, 1983, describes a number of leukotriene A4 derivative analogues having a cyclopropane instead of an epoxide ring, particularly 5,6-methanoleukotriene A4 analogues, as effective 5-lipoxygenase inhibitors. J. J. Voorhees, et al., "Leukotrienes and other Lipoxygenase Products in the Pathogenesis and Therapy of Psoriasis and Other Dermatoses," Arch. Dermatol., Vol. 119, 541-47, July, 1983 list the following compounds as inhibiting the 5- and/or 12-lipoxygenase pathways: flavonoids, e.g. rutin or quercetin, ETYA (5,8,11,14 eicosatraynoic acid) and other acetylenic analogues of arachadonic acid, U-60, 257, a prostaglandin-type compound, NDGA, BW 755C, a pyrazoline derivative, timegadine, 5,6-methanoleukotriene A, and AA 861, a benzoquinone derivative.
Lipoxygenase has been shown to be an iron-containing enzyme, and H. W. Chan in "Soya-bean Lipoxygenase: an Iron-containing Dioxygenase," Biochimica et Biophysica Acta, 327, pp. 32-35, 1973, describes the chelators diphenylthiocarbazone, 1,10-phenanthroline, 2,2'-dipyridyl, 3-hydroxyquinoline, KCN and EDTA as inhibitors of soybean lipoxygenase. J. E. Greenwald, et al., in "Role of Ferric Iron in Platelet Lipoxygenase Activity," Bioch. and Bioph. Res. Communications., Vol. 96, No. 2, pp. 817-822, Sept. 30, 1980, describe the ability of EDTA, EGTA, ferron and orthophenanthrolene to inhibit human platelet lipoxygenase as being in direct correlation with the avidity of these compounds for ferric ion.
M. Hamberg, et al., in "On the Specificity of the Oxygenation of Unsaturated Fatty Acids Catalyzed by Soybean Lipoxidase," J. Biol. Chem., Vol. 242, No. 22, pp. 5329-5335, November, 1967, describe the stereo-specificity of enzymatic attack on eicosatrienoic acids.
Arachidonic acid derivatives through the lipoxygenase pathway and their physiological effects have been discussed in a number of recent publications. Several key articles discussing the subject are: N. Nelson, et al., "Prostaglandins and the Arachidonic Acid Cascade," Chem. & Eng. News, Vol. 60, p. 30, Aug. 16, 1982; B. Samuelsson, et al., "Introduction of a Nomenclature: Leukotrienes," Prostaglandins, Vol. 17, No. 6, pp. 785-87, June, 1979; B. Samuelsson, "Leukotrienes: Mediators of Immediate Hypersensitivity Reactions and Inflammation," Science, Vol. 220, pp. 568-75, May 6, 1983; and R. H. Green, et al., "Leukotrienes," Tetrahedron, Vol. 39, No. 10, pp. 1687-1721, 1983. These chemicals have been reported as important in the promotion of skin tumors by TPA, in the promotion of chemotaxis of polymorphonuclear leukocytes in inflammation, in the promotion of the release of slow reacting substances of anaphylaxis, promotion of release of neutrophil lyosomal enzyme, promotion of release of glucose-induced insulin secretion, promotion of histamine release, stimulation of colonic secretions, stimulation of degranulation of neutrophils, and stimulation of thromboxane, prostaglandins and other cyclooxygenase pathway derivatives of arachidonic acid.
None of the foregoing prior art describes the ability of the compounds of this invention to inhibit lipoxygenase.